Transition anti Felkin

The factors that control the stereochemical outcome of such rections can be illustrated by additions of enantiomeric allenylzinc reagents to (S)-lactic aldehyde derivatives [114]. The matched S/S pairing proceeds via the cyclic transition state A in which addition to the aldehyde carbonyl assumes the Felkin-Anh orientation with an anti arrangement of the allenyl methyl and aldehyde substituents (Scheme 9.29). The alternative arrangement B is disfavored both by the anti-Felkin-Anh arrangement and eclipsing of the allenylmethyl and aldehyde substituents. 

This interaction can be envisioned to stabilize the transition state leading to the observed major anti-Felkin diastereomer 75a. 

Normant and Poisson prepared allenylzinc bromide reagents from TMS acetylenes along the lines of Epsztein and coworkers5, by sequential lithiation with s-BuLi to yield a lithiated species, and subsequent transmetallation with ZnBr2 (equation 35)27,28. Additions to racemic /J-silyloxy aldehydes proceed with low diastereoselectivity to afford mixtures of the anti,anti and anti,syn adducts (Table 17). The latter adducts are formed via an anti Felkin-Anh transition state. Additions to the racemic IV-benzylimine analogs, on the other hand, proceed with nearly complete Felkin-Anh diastereoselectivity to yield the anti,anti amino alcohol adducts (Table 18). 

On the other hand, with heterosubstituted chiral aldehydes, the product distribution for the reaction with methyl ketone enolates is strongly influenced by the nature of the metal, the nature of the heteroatom and its position within the molecule. A chair-like transition state explained the formation of the Felkin adduct, while a boat-like transition state was invoked for the formation of the anti-Felkin adduct. However, this assumption was recently challenged by Roush and coworkers using deuterated pinacolone lithium enolate565. Performing a set of aldolizations with chiral and non chiral aldehydes led these authors to show that the isomeric purity of the enolate correlates almost perfectly with the ratio and pattern of deuterium labeling in the 2,3-an/t-aldol formed consistent with a highly favoured chair-like transition state (Scheme 115). 

There is a dichotomy in the sense of syn-anti diastereofacial preference, dictated by the bulkiness of the migrating group [94]. The sterically demanding silyl group results in syn diastereofacial preference but the less demanding proton leads to anti preference (Sch. 35). The anti diastereoselectivity in carbonyl-ene reactions can be explained by the Felkin-Anh-like cyclic transition-state model (Ti) (Sch. 36). In the aldol reaction, by contrast, the now inside-crowded transition state (Ti ) is less favorable than Tg, because of steric repulsion between the trimethylsilyl group and the inside methyl group of aldehyde (Ti ). The syn-diastereofacial selectivity is, therefore, visualized in terms of the anti-Felkin-like cyclic transition-state model (T2 )-... 

The reaction of both ( )- and (Z)-butenylindium bromides with a-alkoxy aldehydes has been examined to assess the direction and sense of both relative and internal stereoinduction. (Scheme 10-100). High selectivities for the 2>A-synlA,5-anti diastereomers are observed in the reaction of the Z-2-(bromomethyl)-2-butenoate (293) with ehiral aldehydes 294. The stereochemical outcome of the reaction is believed to result from reaction through transition structure xxvi. As the size of the R substituent increases only modest erosion of the coupling diastereoselectiv-ities is observed. This is reminiscent of the anti-Felkin selectivity observed with (Z)-2-butenylboronates with chiral aldehydes (Section 10.4.2.1). 

The preference for the (Z)-crotylboronate reagent 4 to generate the anti-Felkin homoallylic alcohols 31 and 38 in reaction with a-methyl chiral aldehydes 25 and 32 (Table 11-1) is rationalized by transition state 43, where the R substituent of the aldehyde occupies the least sterically demanding a-carbon position, anti to the forming C-C bond, while the hydrogen occupies the most sterically demanding... 

The diastereoselectivity of these reactions is consistent with product formation occurring through transition state 137, where the reactive conformation of the aldehyde in the transition state (corresponding to the normal Felkin-Anh model) minimizes steric interactions with the allylstannane as well as the 1,3-dipole interactions of the aldehyde and the /(-alkoxy group. The allylation reaction of the 2,3-syn aldehyde 138, however, with allyltri-n-butylstannanes 98, generates the anti-Felkin adducts 139 preferentially (Eq. (11.9)) [93], The stereochemistry of these reactions is consistent with product formation occurring preferentially through transition state 140, in which 1,3-dipole interactions of the aldehyde and the P-... 

In reactions of a-methyl chiral aldehydes with achiral (Z)-crotylboronates, the anti-Felkin adduct (cf. 107b) is favored (for further discussion see Section 11.2) [3, 65]. In the double asymmetric reaction of 97b and (S,S)-213, the anti,syn-di-propionate 107b is obtained with high selectivity (selectivity=95 5). The stereochemistry of 107b is consistent with product formation via the matched anti-Felkin transition state 247. Finally, the, vyn,5y -dipropionate 106c is obtained as the major product from the mismatched reaction of the TBDPS-protected aldehyde 97c with (f ,R)-(Z)-213 this reaction, however, is not sufficiently stereoselective to be synthetically useful (selectivity = 64 36). The mismatched transition state... 

The L-talo and L-gulo adducts 447 and 449 were obtained with very high stereoselectivity (no other diastereomers reported) from the reaction of aldehyde 444 with the [y-(alkoxy)allyl]indium reagents generated from (5)-230a and (R)-230a, respectively. In these double asymmetric reactions, reagent control is clearly dominant. The stereochemistry of adduct 447 is rationalized by the Felkin transition state 448 while the stereochemistry of adduct 449 is rationalized by the anti-Felkin transition state 450 [275]. 

Figure 5.7. Analysis of possible transition structures for the aldol addition in Scheme 5.26 (a) The observed topicity (b) boat transition structure postulated by Masamune [127] (c) gauche pentane interaction that destabilizes the Cram (or Felkin-Anh) selectivity of the aldehyde (d) anti-Cram (anti Felkin-Anh) addition via a chelated chair [123].

Stabilized by a 2,3-P,3,4-M gauche pentane interaction (c/ Figure 5.5), as indicated in Figure 5.7c. Roush suggests that an anti Felkin-Anh (anti-Cram) chair transition structure more adequately explains the facts, as shown in Figure 5.7d [123]. 

In order to reverse the diastereoselectivity in the aldol reaction, the Lewis acid-catalyzed silyl enol ether addition (73) (Mukaiyama aldol reaction) was examined. Since the Mukaiyama aldol reaction is assumed to be proceeded via an acyclic transition state, a chelation controled aldol reaction of the a-alkoxy aldehyde should be possible (74). In the presence of TiCU, the silyl enol ether derived from 14 was reacted with aldehyde 13, followed by desilylation to afford the desired anti-Felkin product 122a as a single adduct (Scheme 21). Based on precedents for chelation-controlled Mukaiyama aldol reaction (74), the exceptional high selectivity in this reaction would be accounted for by chelation of TiCl4 with the C23-methoxy group of the aldehyde 13 (eq. 13). On the other hand, when the lithium enolate derived from 14 was treated with the aldehyde 13, followed by desilylation, it gave a 1 4 ratio of the two epimers in favour of the undesired (22S)-aldol product... 

Dipropionates are available through the reaction of the (. -and (2)-crotylboronates 2 and 3 with a-methyl-P-hydroxy aldehydes. The syn,anti-dipropionate 43a emerges as the major product with 97 3 selectivity from the matched crotylation reaction of aldehyde 40a with (R,R)-2. This is the intrinsically favored adduct, and its formation can be rationalized via the Felkin transition state F. The antAanh-dipropionate 44b is the major adduct (selectivity = 90 10) of the mismatched reaction of aldehyde 40b and 2. Its formation can be rationalized via anti-Felkin transition state G and is an example of a reagent-controlled reaction. 

In reactions of a-methyl chiral aldehydes with (.. -enolates and Type (2)-crotylmetal reagents like 3, the anti-Felkin addition product is favored due to unfavorable syn-pentane interactions in the Felkin transition state. Thus, in the matched reaction, the (S,5)-3 reagent reacts with aldehyde 40a to provide the anh, syn-dipropionate 45 with 95 5 selectivity. The stereochemical outcome of the reaction can be rationalized by anti-Felkin transition state H, where the nucleophile must approach near the methyl substituent. The mismatched reaction between aldehyde 40b and (R,R)-3 provides a mixture of dipropionates where the syn,syn-dipropionate 46 is only modestly favored (64 36 = sum of all other diastereomers). Transition state I, that rationalizes the formation of the major product, is less favorable as the nucleophile must approach the carbonyl carbon past the larger R substituent. 

Since equatorial attack is roughly antiperiplanar to two C-C bonds of the cyclic ketone, an extended hypothesis of antiperiplanar attack was proposed39. Since the incipient bond is intrinsically electron deficient, the attack of a nucleophile occurs anti to the best electron-donor bond, with the electron-donor order C—S > C —H > C —C > C—N > C—O. The transition state-stabilizing donor- acceptor interactions are assumed to be more important for the stereochemical outcome of nucleophilic addition reactions than the torsional and steric effects suggested by Felkin. 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

The mismatched R/S pairing could lead to the anti,syn adduct through transition state C and the syn,anti adduct via D (Scheme 9.30). The former pathway entails non-Felkin-Anh addition but anti disposed methyl and aldehyde substituents. Transition state D proceeds through the Felkin-Anh mode of carbonyl addition but requires eclipsing of the methyl and aldehyde substituents. This interaction is the more costly one and thus disfavors the syn,anti adduct. 

Obviously, the nature of the organocopper reagent is an important factor with respect to the stereochemical outcome of the cuprate addition. This is nicely illustrated for the cuprate addition reaction of enoate 75 (Scheme 6.15). Here, lithium di-n-butylcuprate reacted as expected by way of the modified Felkin-Anh transition state 77 (compare also 52), which minimizes allylic A strain, to give the anti adduct 76 with excellent diastereoselectivity [30]. Conversely, the bulkier lithium bis-(methylallyl)cuprate preferentially yielded the syn diastereomer 78 [30, 31]. It can be argued that the bulkier cuprate reagent experiences pronounced repulsive interactions when approaching the enoate system past the alkyl side chain, as shown in transition state 77. Instead, preference is given to transition state 79, in which repulsive interactions to the nucleophile trajectory are minimized. 

For a cuprate addition reaction to a diester derivative such as 88, it might be expected that the anti addition product would be favored, since a pronounced allylic strain in these substrates along modified Felkin-Anh lines should favor transition state 52 (see Fig. 6.1). However, experiments produced the opposite result, with the syn product 89 being obtained as the major diastereomer (Scheme 6.18) [36, 37]. 

Felkin and co-workers model correctly predicts the degree of stereoselectivity as a function of the R group and does not require supplementary hypotheses when applied to cyclohexanones. They suggested that torsional repulsions are important, even between bonds only partially formed. To minimize torsional strain, the chiral carbon atom and the carbonyl adopt a staggered conformation in the transition state. Substituent L is anti to the nucleophile, which can then attack with minimal hindrance. To explain the preference for 1 over 2, Felkin and co-workers suggested that M and S interact more strongly with R than O. 

Once the most reactive substrate conformations are known, it remains to look for the best approach of the nucleophile. An anti attack is promoted by a favorable secondary overlap between the nucleophile and o (C L), which is shown by the double arrow. Syn attack is disfavored, both by a negative secondary overlap (wavy line) and by the eclipsed relationship between C L and Nu---C (Figure 6.6). To summarize, the Felkin transition states are favored because they correspond to the best trajectories for attacking the most reactive conformations. 

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